The present invention relates to novel parenteral solutions containing 3-diethylaminoethoxybenzoylbenzofurans having the following structural formula:
Wherein R1 is alkyl, R2 is hydrogen or methyl, NR2 is hydrogen or methyl, NR3 is dimethylamino, diethylamino, dipropylamino, piperidino, pyrrolidino or morpholino, and Y and Y1 are hydrogen, iodo- or bromo-. More particularly, the present invention relates to a parenteral solution suitable for intravenous administration containing as active ingredient 2-n-butyl-3-(3,5-diiodo-4-β-N-diethylaminoethoxy-benzoyl)benzofuran (hereinafter amiodarone).
Amiodarone has been approved in an oral tablet form (Cordarone®) for the treatment of life-threatening ventricular tachyarrhythmias in the United States since 1985. This drug is useful not only in treating these arrhythmias but also in treating less severe ventricular arrhythmias and many supraventricular arrhythmias including atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways.
To treat arrhythmias, the compound may be administered in oral dosage forms such as in the form of a 200 mg tablet, or it may be administered in the form of an intravenous solution. Please see, for example, Escoubet, B. et al., “Suppression of Arrhythmias Within Hours After Single Oral Dose of Amiodarone and Relation to Plasma and Myocardial Concentrations”, Am. J. Cardiol., (1985), 55:696-702, Mostow et al., “Rapid Suppression of Complex Ventricular Arrhythmias With High-Dose Oral Amiodarone”, Circulation, (1986), 73:1231-8, Morady et al., “Intravenous Amiodarone in the Acute Treatment of Recurrent symptomatic Ventricular Tachycardia”, Am. J. Cardiol., (1983), 51:156-9 and Kadish et al. “The Use of Intravenous Amiodarone in the Acute Therapy of Life-Threatening Tachyarrhythmias”. Progress in Cardiovascular Diseases, (1989), 31:4, 281-294.
Amiodarone is practically insoluble or slightly soluble in an aqueous solvent at very low concentrations. It is difficult to formulate a dosage from suitable for intravenous administration. To aid the dissolution in water, for example, a surfactant has been suggested. Thus, the prior art intravenous dosage form for this compound termed I.V. Cordarone, comprises amiodarone dissolved in a solvent comprising polysorbate 80 available under the tradename Tween-80, and benzyl alcohol. Prior art intravenous solutions of amiodarone will be designated IV Cordarone herein.
However, the use of this dosage form is highly undesirable because it exhibits deleterious cardiovascular effects attributable to the detergent. For example, Torres-Arrault et al. reported in Journal of Electrocardiology, 17 (2), 1984, pp 145-152 that Tween-80 is a potent cardiac depressant and causes hypotension in a dog. See also Gough et al., “Hypotensive Action of Commercial Intravenous Amiodarone and Polysorbate 80 in Dogs”, Journal of Cardiovascular Pharmacology, (1982), 375-380.
Kosinzki, et al., Am J. Cardiol., (1984) 4:565-70 report that intravenous amiodarone (IV Cordarone) can result in significant impairment of left ventricular performance in patients with preexisting left ventricular dysfunction. After acute intravenous bolus administration, patients with a left ventricular ejection fraction greater than 0.35 experienced improved cardiac performance due to both acute and chronic peripheral vasodilation. However, patients with a lower ejection fraction developed a 20% decrease in cardiac index and clinically significant elevation of right heart pressures after acute bolus administration.
Remme et al., Am Heart J., (1991) 122:96-103 report that intravenous amiodarone caused a 15% reduction in blood pressure and an 18% increase in heart rate, and a progressive reduction in contractility (Vmax) with a rise in left ventricular end diastolic pressure.
Bopp et al., J. Cardio. Pharmacol., (1985) 7:286-289 report that IV Cordarone caused a decrease in the ejection fraction, an increase in pulmonary wedge pressure and a 15% decease in dP/dt, and a 12% decrease in left ventricular work.
Each of the above three references discuss the effects of intravenous amiodarone (IV Cordarone), i.e., amiodarone solubilized for intravenous administration using polysorbate 80 and benzyl alcohol. Previously 2-N-butyl-3-(3,5-diiodo-4-β-N-diethylamino-ethoxybenzoyl)benzofuran (amiodarone) was prepared for solubilization using an acetate buffer. In practice amiodarone HCl, which may be purified and crystalline can be dissolved in a buffer system comprising a weak acid and a salt of the weak acid, and more particularly a combination of acetic acid and sodium acetate having a pH below 4.0 and in particular at a range of about 3.5 to 3.8 with a molar concentration of about 0.05 to about 0.1 M. An effective antiarrhythmic amount of amiodarone eg: about 25 to 75 mg/ml is mixed together with buffer and heated to a temperature not to exceed about 75° C. until a solution is complete. This process has the drawback of requiring a heating and cooling stage in the manufacture process and yields an acetic solution that may give rise to a venous phlebitis at the site of intravenous administration.